In recent years, various attempts have been made to stimulate bone growth. These approaches have not been particularly successful, and as a consequence have not as yet received broad acceptance by either the professional (i.e., medical) or lay (i.e., patient) community. Further, this lack of effectiveness has resulted in a reluctance of the third-party payer community (e.g., insurance companies and HMO's) to offer reimbursement, so that commercialization of such stimulation technologies has been stalled.
A number of issued patents disclose methods and apparatuses to biophysically treat bone and other musculoskeletal tissue. For example, Kaufman et al., U.S. Pat. No. 5,309,808 disclose apparatus and method for therapeutically treating and/or quantitatively evaluating bone tissue in vivo, by subjecting bone to an ultrasonic signal pulse of finite duration, and involving a composite sine-wave signal consisting of plural discrete frequencies. These frequencies are spaced in the ultrasonic region to approximately 2 MHz; the excitation signal is repeated substantially in the range 1 to 1000 Hz. In a closely related patent, Kaufman et al., U.S. Pat. No. 5,458,130, the same inventors extend the apparatus and method to the treatment to musculoskeletal tissue in general. In another patent by the same inventors, Kaufman et al., U.S. Pat. No. 5,547,459 disclose apparatus and method for therapeutically treating bone tissue in vivo, by subjecting bone to an-ultrasonic sinusoidal signal pulse peculiarly modulated by a sinusoidal signal with a frequency between about 0 Hz and 25 kHz.
Duarte, U.S. Pat. No. 4,530,360 discloses apparatus and a method of using ultrasonic energy for therapeutic treatment of bone tissue in vivo, using a pulsed sine wave at substantially a single frequency within the range 1.3 to 2.0 MHz, and at a pulse repetition rate of 100 to 1000 Hz.
McLeod et al., U.S. Pat. Nos. 5,103,806 and 5,191,880 disclose methods for promotion of growth bone tissue and the prevention of osteopenia, using mechanical loading of the bone tissue. In both patents, the inventors apply a mechanical load to the bone tissue at a relatively low level on the order of between about 50 and about 500 microstrain, peak to peak, and at a relatively high frequency in the range of about 10 and 50 hertz.
Bassett et al., U.S. Pat. No. 4,928,959 disclose method and device for providing active exercise treatment for a patient suffering from a bone disorder. A patient is subjected to an impact load in order to stimulate bone growth, with an impact load sensor being used to monitor the treatment strength.
Numerous other patents disclose methods for stimulating bone growth relying on the generation of electromagnetic signals. For example, Ryaby et al. U.S. Pat. Nos. 4,105,017 and 4,315,503 describe methods for promoting bone healing in delayed and nonunion bone fractures, using an asymmetric pulsed waveform. In U.S. Pat. No. 4,993,413, McLeod et al. disclose method and apparatus for inducing a current and voltage in living tissue to prevent osteoporosis and to enhance new bone formation. They disclose the use of a symmetrical low frequency and low intensity electromagnetic signal substantially in the range of 1-1000, hertz. In Liboff et al., U.S. Pat. No. 5,318,551 (and others), methods are disclosed which incorporate the combined use of a static and time-varying magnetic field to stimulate bone healing and growth. Specific amplitudes and frequencies are disclosed for optimal enhancement of bone growth, based on the theory of "ion-cyclotron resonance."
Non-biophysical methods, i.e., methods which use a biochemical compound (or generically a "bone growth factor") to stimulate bone growth have also been described. For example, Ammann et al., U.S. Pat. No. 5,604,204 disclose method for inducing bone growth using a bone growth factor composition known as TGF-.beta., in an animal, locally at a bone site where skeletal tissue is deficient. The TGF-.beta. is contained in a "pharmaceutically acceptable carrier" in an amount effective to induce bone growth at the bone site.
Dunstan et al., U.S. Pat. No. 5,656,598 disclose method involving therapeutic (biochemical) compositions for the prevention and treatment of pathological conditions involving bone and dental tissue. The invention achieves its objectives by administering a fibroblast growth factor (FGF-1) to an animal or human in need of such treatment.
Oppermann et al., U.S. Pat. No. 5,354,557 and U.S. Pat. No. 5,814,604, disclose methods involving osteogenic devices. (The use of the term "devices" should be understood to denote a biochemical compound or bone growth factor in an appropriate matrix for delivery to the bone.) The osteogenic devices are comprised of a matrix containing substantially pure naturally-sourced mammalian osteogenic protein. The Patents also disclose DNA and amino acid sequences for novel polypeptide chains useful as subunits of dimeric osteogenic proteins, and methods of using the osteogenic devices to mimic the natural course of endochondral bone formation in mammals. The inventors also disclose methods of producing osteogenic proteins using recombinant DNA technology.
Balazs et al., U.S. Pat. No. 5,128,326, disclose systems based on hyaluronans derivatives, as well as methods for preparing same. Such systems are useful for treatment of cartilage tissue.
Falk et al., U.S. Pat. No. 5,792,753 disclose a pharmaceutical composition which contains a drug that inhibits prostaglandin synthesis, and also contains an amount of a form of hyaluronic acid. The composition is topically administered to the skin and is useful for the treatment of cartilage as it relates to arthritis.
Wang et al., U.S. Pat. No. 4,877,864, disclose human and bovine bone and cartilage inductive (biochemical) factors. Such factors may be produced by recombinant techniques and may be useful for treatment of various musculoskeletal tissue defects.
The prior art, exemplified by the references that have been briefly discussed, have used either biophysical or biochemical approaches, to promote bone growth, bone ingrowth and bone healing, or other musculoskeletal tissue healing or growth. In either case, that is, in the biophysical approach (including for example, ultrasound methods), or in the biochemical approach (including, for example, bone growth factors such as TFG-.beta.), treatment has not been effective enough to lead to widespread use. However, the present inventors have discovered how to dramatically enhance the efficacy of such therapeutic methods for bone growth and other musculoskeletal tissue healing, taking advantage of the uniquely synergistic nature associated with the two basic approaches.